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A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival ( PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma ( RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio ( HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group ( HR, 0·753). For patients <70 years the overall response rate ( ORR) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. Trial Registration : clinicaltrials.gov identifier: NCT01080391. [ABSTRACT FROM AUTHOR]

A population pharmacokinetic (PK) model and exposure-response (E-R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m2 (20 mg/m2 in cycle 1 and, if tolerated, escalated to 56 mg/m2 on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant. Despite inclusion of different populations (relapsed or relapsed/refractory), treatments (carfilzomib monotherapy or combination therapy), infusion lengths (2 to 10 minutes or 30 minutes), and different doses, the E-R analysis of efficacy showed that after adjusting for baseline characteristics, higher area under the concentration-time curve was associated with improved overall response rate (ORR), from 15 to 20/56 mg/m2. No positive relationships between maximum concentration and ORR were identified, indicating that ORR would not be expected to be impacted by infusion length. For safety end points, no statistically significant relationship between exposure and increasing risk of adverse events was identified. The results of an E-R analysis provided strong support for a carfilzomib dose at 20/56 mg/m2 as a 30-minute infusion for monotherapy and combination therapy. This article illustrates an example of application of E-R analysis to support labeling dose recommendation in the absence of extensive clinical data. [ABSTRACT FROM AUTHOR]

Objectives: Arterial remodeling has been suggested as the predominant factor in restenosis. However, the time course and morphometric factors that determine whether remodeling occurs remain unclear. We hypothesized that arterial remodeling does not occur in all arteries following balloon injury and is dependent on neoadventitial formation. Methods: Using single (SI) and double (DI) balloon injury of Yorkshire porcine coronary arteries we examined changes in morphometry 3, 7, 14, and 28 days following balloon injury. Results: In both SI and DI arteries, the neoadventitia (NAD) area expanded by day 3 and was the first compartment to increase following injury. In SI arteries lumen area (LA) decreased between day 3 and 14 while in DI arteries, there was significantly less loss in LA. In SI arteries, contracture of the area circumscribed by the external elastic lamina (EEL), which occurred predominantly between day 7 and 14, accounted for 67% of the loss of LA. Conclusions: Accumulation of NAD appears to be the earliest change in the vessel wall following balloon injury of normal or previously injured arteries and precedes the growth of the I+M (intima and media). The predominant mechanism for lumenal narrowing following single balloon injury of a normal artery is remodeling. In contrast, remodeling does not occur in DI arteries, possibly due to differences in the degree of adventitial fibrosis of normal and injured arteries. [ABSTRACT FROM PUBLISHER]

Presents a case report of tuberculosis of the extrahepatic biliary system in a man. Medical history of the man; Epithelioid cell granuloma found after histopathological examination; Modes of infection of the biliary duct.

Introduction cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of IL-17 and IL-21. A reduction in the regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an oral Rho kinase 2 (ROCK2) selective inhibitor. In vitro data demonstrate KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards Treg. Methods 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy were treated in 28-Day cycles until disease progression. The primary endpoint is overall response rate (ORR) (partial/complete response) per 2014 NIH criteria. Additional endpoints include duration of response (DOR), corticosteroid (CS) dose reductions, Lee Symptom Scale (LSS) score and PD. Blood samples were collected at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. Intracellular expression of IL-17A and FOXP3 was determined by flow cytometry. Results Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, time from cGVHD diagnosis to KD025 treatment of 19 months, and 3 prior regimens. Median duration of treatment was37 (C1) and 33 (C2) weeks. KD025 demonstrated ORR of 65% in C1 and 63% in C2. Responses were rapid (76% at first assessment at 8 weeks) and durable (≥20 weeks) in 82% (C1) and 50% (C2) of responders. Median CS dose was reduced 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score. Common AEs were increased LFTs 42%, URI 33%, anemia 27%, nausea 24%, diarrhea 24% and fatigue 21%. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 pts, none considered related to KD025. There was no apparent increased risk of infection. Exploratory PD analyses revealed an early increase in the percentage of CD4+ Treg cells by C2D1 with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C6D25. Conclusion KD025 achieved responses with little toxicity. Responses are clinically meaningful with durability, reductions in CS doses and improvement in LSS score. PD data indicate KD025 may restore the Th17/Treg balance. [ABSTRACT FROM AUTHOR]

Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481., (© 2021 by The American Society of Hematology.)

Objective: To assess the economic value of carfilzomib (Kyprolis), this study developed the Kyprolis Global Economic Model (K-GEM), which examined from a United States (US) payer perspective the cost-effectiveness of carfilzomib-lenalidomide-dexamethasone (KRd) versus lenalidomide-dexamethasone (Rd) in relapsed multiple myeloma (RMM; 1-3 prior therapies) based on results from the phase III ASPIRE trial that directly compared these regimens., Methods: A partitioned survival model that included three health states of progression-free (on or off treatment), post-progression, and death was developed. Using ASPIRE data, the effect of treatment regimens as administered in the trial was assessed for progression-free survival and overall survival (OS). Treatment effects were estimated with parametric regression models adjusting for baseline patient characteristics and applied over a lifetime horizon. US Surveillance, Epidemiology and End Results (1984-2014) registry data were matched to ASPIRE patients to extrapolate OS beyond the trial. Estimated survival was adjusted to account for utilities across health states. The K-GEM considered the total direct costs (pharmacy/medical) of care for patients treated with KRd and Rd., Results: KRd was estimated to be more effective compared to Rd, providing 1.99 life year and 1.67 quality-adjusted life year (QALY) gains over the modeled horizon. KRd-treated patients incurred $179,393 in total additional costs. The incremental cost-effectiveness ratio (ICER) was $107,520 per QALY., Limitations: Extrapolated survival functions present the greatest uncertainty in the modeled results. Utilities were derived from a combination of sources and assumed to reflect how US patients value their health state., Conclusions: The K-GEM showed KRd is cost-effective, with an ICER of $107,520 per QALY gained against Rd for the treatment of patients with RMM (1-3 prior therapies) at a willingness-to-pay threshold of $150,000. Reimbursement of KRd for patients with RMM may represent an efficient allocation of the healthcare budget.

Objective: To assess the difference in resource utilisation between lithium and valproate treatment groups from the VALID study., Methods: A modelled economic study was conducted as an appendage to the VALID study, an international, randomised, open-label, parallel-group, 12-week, equivalence study in patients with bipolar I disorder experiencing a manic/mixed episode, compared the efficacy and safety of valproate against that of lithium. The difference in health resource utilisation between the treatment groups was analysed based on information collected from a standardised questionnaire., Results: Efficacy and tolerability of valproate and lithium were shown to be comparable in the management of bipolar disorder in the VALID study. Cost analysis was based on information for 138 (35.5% male, mean age: 37.73 years) and 131 (45.8% male, mean age: 38.98 years) patients from lithium and valproate treatment groups, respectively. The groups differed in the number of hospital visits (503 vs. 421), outpatient visits (15 vs. 2), and number of work days lost (907 vs. 514.5) due to bipolar disorder. All differences were in favour of the valproate treatment group. In the modelled analysis and subsequent sensitivity analyses, the total cost saving was calculated to be US$199,322 (range: US$37,629-$226,903). This would translate into a cost saving of US$1444 per patient, or a cost saving of US$6278 per patient per year (range: US$1185-$7145 per patient per year)., Limitations: The present study suffers from the limitations inherent in any economic evaluation that uses data from multicentre clinical trials with potential variations in treatment provision as well as the theoretical bias from an open-label study design. The study sample size had also limited statistical power to detect moderate differences in total medical costs, given the large variances often observed on cost variables., Conclusions: The use of valproate over lithium is likely to result in substantial cost savings to the healthcare system and reduce the financial burden to patients.